nach oben

Neurogenetics

Erschienen in:

27.01.2024 | Original Article

Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A

verfasst von: Namanpreet Kaur, Khyati Arora, Periyasamy Radhakrishnan, Dhanya Lakshmi Narayanan, Anju Shukla

Erschienen in: Neurogenetics | Ausgabe 2/2024

Einloggen, um Zugang zu erhalten

Abstract

Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.

Nur mit Berechtigung zugänglich

van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WF, Hoogenraad F, Valk J (1995) Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 37(3):324–334. https://doi.org/10.1002/ana.410370308CrossRefPubMed

Singhal BS, Gursahani RD, Udani VP, Biniwale AA (1996) Megalencephalic leukodystrophy in an Asian Indian ethnic group. Pediatr Neurol 14(4):291–296. https://doi.org/10.1016/0887-8994(96)00048-3CrossRefPubMed

van der Knaap MS, Lai V, Köhler W, Salih MA, Fonseca MJ, Benke TA, Wilson C, Jayakar P, Aine MR, Dom L, Lynch B, Kálmánchey R, Pietsch P, Errami A, Scheper GC (2010) Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol 67(6):834–837. https://doi.org/10.1002/ana.21980CrossRefPubMed

López-Hernández T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S, Duarri A, Schulte U, Fakler B, Nunes V, Scheper GC, Martínez A, Estévez R, van der Knaap MS (2011) Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet 88(4):422–432. https://doi.org/10.1016/j.ajhg.2011.02.009CrossRefPubMedPubMedCentral

Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, Mejaski-Bosnjak V, van der Maarel SM, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS (2001) Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 68(4):831–838. https://doi.org/10.1086/319519CrossRefPubMedPubMedCentral

Passchier EMJ, Kerst S, Brouwers E, Hamilton EMC, Bisseling Q, Bugiani M, Waisfisz Q, Kitchen P, Unger L, Breur M, Hoogterp L, de Vries SI, Abbink TEM, Kole MHP, Leurs R, Vischer HF, Brignone MS, Ambrosini E, Feillet F, Born A. P., … van der Knaap MS (2023) Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema. Brain : a journal of neurology, 146(8), 3444–3454https://doi.org/10.1093/brain/awad146

Shi Z, Yan HF, Cao BB, Guo MM, Xie H, Gao K, Xiao JX, Yang YL, Xiong H, Gu Q, Li M, Wu Y, Jiang YW, Wang JM (2019) Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models. World J Pediatrics : WJP 15(5):454–464. https://doi.org/10.1007/s12519-019-00284-wCrossRefPubMed

Arnedo T, Aiello C, Jeworutzki E, Dentici ML, Uziel G, Simonati A, Pusch M, Bertini E, Estévez R (2014) Expanding the spectrum of megalencephalic leukoencephalopathy with subcortical cysts in two patients with GLIALCAM mutations. Neurogenetics 15(1):41–48. https://doi.org/10.1007/s10048-013-0381-xCrossRefPubMed

Guo MM, Jiang YW, Xie H, Wu Y, Shang J, Gu Q, Wu XR, Wang JM (2012) Zhonghua er ke za zhi = Chinese journal of pediatrics 50(12), 895–898

10.

Abdel-Salam GM, Abdel-Hamid MS, Ismail SI, Hosny H, Omar T, Effat L, Aglan MS, Temtamy SA, Zaki MS (2016) Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect. Metab Brain Dis 31(5):1171–1179. https://doi.org/10.1007/s11011-016-9861-7CrossRefPubMed

11.

Cao B, Yan H, Guo M, Xie H, Wu Y, Gu Q, Xiao J, Shang J, Yang Y, Xiong H, Niu Z, Wu X, Jiang Y, Wang J (2016) Ten novel mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts and a long-term follow-up research. PLoS ONE 11(6):e0157258. https://doi.org/10.1371/journal.pone.0157258CrossRefPubMedPubMedCentral

12.

Yamamoto T, Shimada S, Shimojima K, Sangu N, Ninomiya S, Kubota M (2015) Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients. Eur J Med Genet 58(9):492–496. https://doi.org/10.1016/j.ejmg.2015.06.008CrossRefPubMed

13.

Vasimuddin M, Misra S, Li, H, & Aluru S (2019) Efficient architecture-aware acceleration of BWA-MEM for multicore systems. In 2019 IEEE International Parallel and Distributed Processing Symposium (IPDPS) (pp. 314–324). IEEE. https://doi.org/10.1109/IPDPS.2019.00041.

14.

Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Van der Auwera GA, Kling DE, Gauthier LD, Levy-Moonshine A, Roazen D, Shakir K, Thibault J, Chandran S, Whelan C, Lek M, Gabriel S, Daly MJ, Neale B, MacArthur DG, Banks E (2017) Scaling accurate genetic variant discovery to tens of thousands of samples bioRxiv, 201178. https://doi.org/10.1101/201178

15.

Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164. https://doi.org/10.1093/nar/gkq603CrossRefPubMedPubMedCentral

16.

Klambauer G, Schwarzbauer K, Mitterecker A, Mayr A, Clevert D-A, Bodenhofer U, Hochreiter S (2012) cn.MOPS: mixture of Poissons for discovering copy number variations in next generation sequencing data with a low false discovery rate. Nucleic Acids Res 40(9):e69. https://doi.org/10.1093/nar/gks003CrossRefPubMedPubMedCentral

17.

Livak KJ, & Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods (San Diego, Calif.), 25(4), 402–408. https://doi.org/10.1006/meth.2001.1262

18.

Brandt T, Sack LM, Arjona D, Tan D, Mei H, Cui H, Gao H, Bean LJH, Ankala A, Del Gaudio D, Knight Johnson A, Vincent LM, Reavey C, Lai A, Richard G, Meck JM (2020) Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants. Genetics Med 22(2):336–344. https://doi.org/10.1038/s41436-019-0655-2CrossRef

19.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Laboratory Quality Assurance Committee ACMG (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30CrossRef

20.

Chung Moh M, Hoon Lee L, Shen S (2005) Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma. J Hepatol 42(6):833–841. https://doi.org/10.1016/j.jhep.2005.01.025CrossRefPubMed

21.

Favre-Kontula L, Rolland A, Bernasconi L, Karmirantzou M, Power C, Antonsson B, Boschert U (2008) GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. Glia 56:633–645. https://doi.org/10.1002/glia.20640CrossRefPubMed

22.

Moh MC, Zhang C, Luo C, Lee LH, Shen S (2005) Structural and functional analyses of a novel ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells. J Biol Chem 280(29):27366–27374. https://doi.org/10.1074/jbc.M500852200CrossRefPubMed

23.

López-Hernández T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernández-Dueñas V, Scheper GC, van der Knaap MS, Casquero P, Ciruela F, Ferrer I, Nunes V, Estévez R (2011) Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet 20(16):3266–3277. https://doi.org/10.1093/hmg/ddr238CrossRefPubMed

24.

Capdevila-Nortes X, Jeworutzki E, Elorza-Vidal X, Barrallo-Gimeno A, Pusch M, Estévez R (2015) Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy. J Physiol 593(18):4165–4180. https://doi.org/10.1113/JP270467CrossRefPubMedPubMedCentral

25.

Arnedo T, López-Hernández T, Jeworutzki E, Capdevila-Nortes X, Sirisi S, Pusch M, Estévez R (2014) Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy. Hum Mutat 35(10):1175–1178. https://doi.org/10.1002/humu.22622CrossRefPubMed

26.

Elorza-Vidal X, Xicoy-Espaulella E, Pla-Casillanis A, Alonso-Gardón M, Gaitán-Peñas H, Engel-Pizcueta C, Fernández-Recio J, Estévez R (2020) Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies. Hum Mol Genet 29(7):1107–1120. https://doi.org/10.1093/hmg/ddaa009CrossRefPubMedPubMedCentral

27.

Newman S, Hermetz KE, Weckselblatt B, Rudd MK (2015) Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. Am J Hum Genet 96(2):208–220. https://doi.org/10.1016/j.ajhg.2014.12.017CrossRefPubMedPubMedCentral

28.

Truty R, Paul J, Kennemer M, Lincoln SE, Olivares E, Nussbaum RL, Aradhya S (2019) Prevalence and properties of intragenic copy-number variation in Mendelian disease genes. Genetics Med 21(1):114–123. https://doi.org/10.1038/s41436-018-0033-5CrossRef

29.

Cohen-Salmon M, El-Amraoui A, Leibovici M, Petit C (1997) Otogelin: a glycoprotein specific to the acellular membranes of the inner ear. Proc Natl Acad Sci USA 94(26):14450–14455. https://doi.org/10.1073/pnas.94.26.14450CrossRefPubMedPubMedCentral

30.

Simmler MC, Cohen-Salmon M, El-Amraoui A, Guillaud L, Benichou JC, Petit C, Panthier JJ (2000) Targeted disruption of otog results in deafness and severe imbalance. Nat Genet 24(2):139–143. https://doi.org/10.1038/72793CrossRefPubMed

31.

Schraders M, Ruiz-Palmero L, Kalay E, Oostrik J, del Castillo FJ, Sezgin O, Beynon AJ, Strom TM, Pennings RJ, Zazo Seco C, Oonk AM, Kunst HP, Domínguez-Ruiz M, García-Arumi AM, del Campo M, Villamar M, Hoefsloot LH, Moreno F, Admiraal RJ, del Castillo I, … Kremer H (2012) Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. American journal of human genetics, 91(5), 883–889. https://doi.org/10.1016/j.ajhg.2012.09.012

32.

Plagnol V, Curtis J, Epstein M, Mok KY, Stebbings E, Grigoriadou S, Wood NW, Hambleton S, Burns SO, Thrasher AJ, Kumararatne D, Doffinger R, Nejentsev S (2012) A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics (Oxford, England) 28(21):2747–2754. https://doi.org/10.1093/bioinformatics/bts526CrossRefPubMed

33.

Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, Handsaker RE, McCarroll SA, O’Donovan MC, Owen MJ, Kirov G, Sullivan PF, Hultman CM, Sklar P, Purcell SM (2012) Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet 91(4):597–607. https://doi.org/10.1016/j.ajhg.2012.08.005CrossRefPubMedPubMedCentral

Titel: Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A
verfasst von: Namanpreet Kaur
Khyati Arora
Periyasamy Radhakrishnan
Dhanya Lakshmi Narayanan
Anju Shukla
Publikationsdatum: 27.01.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: Neurogenetics / Ausgabe 2/2024
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-024-00743-1

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Nicht Creutzfeldt Jakob, sondern Abführtee-Vergiftung

29.05.2024 Hyponatriämie Nachrichten

Eine ältere Frau trinkt regelmäßig Sennesblättertee gegen ihre Verstopfung. Der scheint plötzlich gut zu wirken. Auf Durchfall und Erbrechen folgt allerdings eine Hyponatriämie. Nach deren Korrektur kommt es plötzlich zu progredienten Kognitions- und Verhaltensstörungen.

Schutz der Synapsen bei Alzheimer

29.05.2024 Morbus Alzheimer Nachrichten

Mit einem Neurotrophin-Rezeptor-Modulator lässt sich möglicherweise eine bestehende Alzheimerdemenz etwas abschwächen: Erste Phase-2-Daten deuten auf einen verbesserten Synapsenschutz.

Sozialer Aufstieg verringert Demenzgefahr

24.05.2024 Demenz Nachrichten

Ein hohes soziales Niveau ist mit die beste Versicherung gegen eine Demenz. Noch geringer ist das Demenzrisiko für Menschen, die sozial aufsteigen: Sie gewinnen fast zwei demenzfreie Lebensjahre. Umgekehrt steigt die Demenzgefahr beim sozialen Abstieg.

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2024

Bi-allelic variants in HCRT cause autosomal recessive narcolepsy

Expanding the clinical and genetic landscape of (developmental) epileptic encephalopathy with spike-and-wave activation in sleep: results from studies of a Turkish cohort

GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review

Gene–gene interaction network analysis indicates CNTN2 is a candidate gene for idiopathic generalized epilepsy

Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families